Synthesis of the 4-arylindole portion of the antitumor agent diazonamide and related studies

Article abstract of DOI:10.1016/S0040-4039(99)02204-2

The synthesis of 6 comprising the CDG rings of the diazonamides was achieved in an overall yield of 75% from commercially available 3. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02204-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 835–838
Synthesis of the 4-arylindole portion of the antitumor agent
diazonamide and related studies
Fiona Chan, Philip Magnus ∗ and Edward G. McIver
Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, Texas 78712, USA
Received 19 October 1999; revised 19 November 1999; accepted 22 November 1999
Abstract
The synthesis of 6 comprising the CDG rings of the diazonamides was achieved in an overall yield of 75% from
commercially available 3. © 2000 Elsevier Science Ltd. All rights reserved.
In the preceding letter we have described the synthesis of the CDEF-rings of the diazonamide A, 1 and
diazonamide B, 2 (Scheme 1).1,2 While the synthesis of the 4-arylindole portion comprising the CDG-
rings has been reported,3 the yields for the formation of the 4-aryl bond is frequently low. Consequently,
we decided to examine the formation of the 4-arylindole using the Suzuki cross coupling reaction4 both
before and after the construction of the indole portion.
Scheme 1.
4-Bromoindole 55 was synthesized from 3 using the Leimgruber–Batcho methodology via the enamine
4 (Scheme 2).6 Suzuki coupling of 5 with 2-methoxyphenyl boronic acid gave 6 in an optimized 48%
yield. Whereas, reversing the sequence and conducting the Suzuki coupling first, gave 7 in 98% yield.
Exposure of 7 to the Leimgruber–Batcho reaction conditions gave 6 (76% from 7).7
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02204-2
tetl 16132

836
Scheme 2.
We have also explored the synthesis of the 4-aryl-2-oxindole 11, which should allow the introduction
of the 2-chloro substituent. Acid hydrolysis of 5 followed by sodium chlorite oxidation8 and esteri-
fication gave 9 (Scheme 3). Suzuki coupling of 9, as for 3, gave 10 (95%), which was reduced with
Zn/EtOH/H2SO4 to give the 2-oxindole 11.
Scheme 3.
While it has been reported that 2-oxindole 17 on treatment with oxalyl chloride/CH2Cl2/25°C
gave 19 (92%) (Eq. (1)),9 we found that this procedure converted 11 into the oxamide derivative

837
14 (>95%). Repeating the literature example, we found that treatment of 2-oxindole 17 with oxalyl
chloride/CH2Cl2/25°C gave a precipitate of 19 (46%) and the filtrate contained 18 (42%). This result
is more in keeping with other observations concerning the reactions of oxalyl chloride and amides.10
Consequently, we examined alternative ways to introduce the 2-chloro and a carbon substituent at C3
into the 2-oxindole 11.
(1)
Treatment of 11 with POCl3/DMF (Vilsmeier reagent) gave the aldehyde 12.11 Oxidation of 12 using
the chlorite procedure gave the acid 13, which, somewhat surprisingly, underwent decarboxylation at
25°C when treated with Et3N/CH2Cl2 to give 15. Since the yield of 12 was rather modest (51%), and the
acid 13 could not be readily activated without concomitant decarboxylation, it was decided to attempt
to convert 11 directly into 15. While standard methods for converting amides into iminochlorides have
been used to transform 2-oxindoles into 2-chloroindoles,12 the yields are low and dimeric by-products are
formed. Indeed, treatment of 11 with POCl3/CH2Cl2 gave a complex mixture of products with only traces
of 15 present. It was found that treatment of 11 with CCl4/PPh3/MeCN under scrupulously anhydrous
reaction conditions using freshly purified reagents and solvent gave a pale yellow solution from which
15 (83%) could be isolated. Without these precautions the reaction mixture turned black, and the yield of
15 was very low.
With a practical synthesis of the 2-chloroindole 15 available we now could examine its conversion
into 16, which had eluded us above. Exposure of 15 to (COCl)2/CH2Cl2 at 25°C gave 16 in 70% yield,
illustrating that the problem in the conversion of 11 into 16 in a single step is the formation of the 2-
chloroindole 15. While we were able to carry out some potentially useful reactions on 16, the 2-chloro
substituent caused a number of problems, and therefore we decided to introduce the chlorine atoms after
the formation of the oxazole rings rather than before. The successful outcome of this strategy is described
in the accompanying letter.
Acknowledgements
The National Institutes of Health, Robert A. Welch Foundation, Merck Research Laboratories and
Novartis are thanked for their support of this research.
References
1. Lindquist, N.; Fenical, W.; Van Duyne, G. D.; Clardy, J. J. Am. Chem. Soc. 1991, 113, 2303–2304.
2. Magnus, P.; McIver, E. G. Tetrahedron Lett, preceding letter.
3. (a) Moody, C.; Doyle, K.; Elliott, M.; Mowlen, T. J. Chem. Soc., Perkin Trans. 1 1997, 2413–2419. (b) Konopelski, J.;
Hottenroth, J.; Oltra, H.; Veliz, E.; Yang, Z.-C. Synlett 1996, 609–611. (c) Boto, A.; Ling, M.; Meek, G.; Pattenden, G.
Tetrahedron Lett. 1998, 39, 8167–8170. (d) Wipf, P.; Yokokawa, F. Tetrahedron Lett. 1998, 39, 2223–2226.
4. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.
5. Moyer, M. P.; Shiurba, J. F.; Rapoport, H. J. Org. Chem. 1986, 51, 5106–5110.

838
6. Batcho, A. D.; Liemgruber, W. US Patent 3,976,639, 1976. Clark, R. D.; Repke, D. B. Heterocycles 1984, 22, 195.
Kozikowski, A. P.; Greco, M. N.; Springer, J. P. J. Am. Chem. Soc. 1982, 104, 7622–7626.
7. Batt, D. G.; Petraitis, J. J.; Sherk, S. R.; Copeland, R. A.; Dowling, R. L.; Taylor, T. L.; Jones, E. A.; Magolda, R. L.;
Jaffee, B. D. Bioorganic & Med. Chem. Lett. 1998, 8, 1745–1750. These authors report the same reactions to make 6 but in
approximately 40% overall yield.
8. Magnus, P.; Gallagher, T.; Schultz, J.; Or, Y.-S.; Ananthanarayan, T. P. J. Am. Chem. Soc. 1987, 109, 2706–2711. Hase, T.
A.; Nylund, E.-L. Tetrahedron Lett. 1979, 2633.
9. Bergman, J.; Carlsson, R.; Sjöberg, B. J. Heterocyclic Chem. 1977, 14, 1123–1134.
10. Bergman, J.; Stålhandske, C. Tetrahedron 1996, 52, 753–770.
11. Showalter, H. D. H.; Sercel, A. D.; Leja, B. M.; Wolfangel, C. D.; Ambroso, L. A.; Elliott, W. L.; Fry, D. W.; Kraker, A. J.;
Howard, C. T.; Lu, G. H.; Moore, C. W.; Nelson, J. M.; Roberts, B. J.; Vincent, P. W.; Denny, W. A.; Thompson, A. M. J.
Med. Chem. 1997, 40, 413–426.
12. Kubo, A.; Nakai, T. Synthesis 1980, 365–366. Bergman, J.; Venemalm, L. J. Org. Chem. 1992, 57, 2495–2497, and
references cited therein.